| Autor: |
Wengert, Eric R., Miralles, Raquel M., Wedgwood, Kyle C. A., Wagley, Pravin K., Strohm, Samantha M., Panchal, Payal S., Idrissi, Abrar Majidi, Wenker, Ian C., Thompson, Jeremy A., Gaykema, Ronald P., Patel, Manoj K. |
| Předmět: |
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| Zdroj: |
Journal of Neuroscience; 11/3/2021, Vol. 41 Issue 44, p9257-9273, 17p |
| Abstrakt: |
SCN8A epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant SCN8A, which encodes the voltagegated sodium channel NaV1.6. To date, it is unclear if and how inhibitory interneurons, which express NaV1.6, influence disease pathology. Using both sexes of a transgenic mouse model of SCN8A epileptic encephalopathy, we found that selective expression of the R1872W SCN8A mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility to audiogenic seizures. Patch-clamp electrophysiology experiments revealed that SST interneurons from mutant mice were hyperexcitable but hypersensitive to action potential failure via depolarization block under normal and seizure-like conditions. Remarkably, GqDREADD-mediated activation of WT SST interneurons resulted in prolonged electrographic seizures and was accompanied by SST hyperexcitability and depolarization block. Aberrantly large persistent sodium currents, a hallmark of SCN8A mutations, were observed and were found to contribute directly to aberrant SST physiology in computational modeling and pharmacological experiments. These novel findings demonstrate a critical and previously unidentified contribution of SST interneurons to seizure generation not only in SCN8A epileptic encephalopathy, but epilepsy in general. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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